Hypertension affects about 20% of the adult population in developed countries. In the adult population aged 60 years or older, this percentage increases to about 60% to 70%. Hypertension also is associated with an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. Although a number of anti-hypertensive drugs are available in various pharmacological categories, the efficacy and safety of such drugs can vary from patient to patient.
Mineralocorticoid receptor antagonists are one class of drugs that can be used to treat hypertension and/or related physiological complications (Jewell, C. W., et al., Cardiovascular & Hematological Agents in Medicinal Chemistry (2006) Vol. 4, pgs. 129-153). Mineralocorticoids, such as aldosterone, are involved in regulating salt and water balance in mammals. Activation of the mineralocorticoid receptor can induce hypertension and cause other detrimental cardiovascular and physiological effects. Two mineralocorticoid receptor antagonists, spironolactone (ALDACTONE™) and eplerenone (INSPRA™), are presently available and indicated for the treatment of hypertension and heart failure (Baxter, J. D., et al., Molecular and Cellular Endocrinology (2004) Vol. 217, pgs. 151-165).
The identification of additional compounds that are mineralocorticoid receptor antagonists is desirable. Such compounds can be used to treat subjects suffering from or susceptible to hypertension and/or related physiological problems and further expand the range of treatment options available for such subjects. Both spironolactone and eplerenone have a steroidal structure. The present invention is particularly directed to mineralocorticoid receptor antagonists that are non-steroidal compounds. Use of a non-steroidal mineralocorticoid receptor antagonist potentially provides certain advantages over a steroidal mineralocorticoid receptor antagonist including, e.g., further improvement in selectivity with respect to the sex hormone receptors; less complex and costly chemical synthesis; and the like.
Non-steroidal compounds useful as mineralocorticoid receptor antagonists have been reported in the literature. For example:
WO 06/076202 (published Jul. 20, 2006) reports a class of imidazole carboxamides as mineralocorticoid receptor antagonists.
WO 06/012642 (published Feb. 2, 2006) reports a class of pyrrole carboxamides as mineralocorticoid receptor antagonists.
WO 04/052847 (published Jun. 24, 2004) reports a class of dibenzosuberanes as mineralocorticoid receptor antagonists.
WO 05/066161 (published Jul. 21, 2005) reports a class of dibenzosuberanes as mineralocorticoid receptor antagonists.
WO 03/078394 (published Sep. 25, 2003) reports a class of 3,3-bisaryl oxindoles as mineralocorticoid receptor antagonists.
WO 05/097118 (published Oct. 20, 2005) reports a class of 4-aryl-1,4-dihydropyridines as mineralocorticoid receptor antagonists.
WO 04/067529 (published Aug. 12, 2004) reports a class of 3-benzyl indoles as mineralocorticoid receptor antagonists.
WO 06/077821 (published Jul. 27, 2006) reports classes of benzoxazine/thiones and tetrahydroquinolines as mineralocorticoid receptor antagonists.
WO 06/010142 (published Jan. 26, 2006) reports a class of aryl benzoxazinones/thiones as mineralocorticoid receptor antagonists.